The main objective of this R01 application is to determine the early gut mucosal sensing and response to HIV infection that induces gut inflammation and support initial viral dissemination and establishes viral reservoirs. Gastrointestinal mucosa is an early target of HIV infection and a site of severe CD4+ T cell depletion and gut epithelial barrier dysfunction, which leads to immune dysfunction and persistent immune activation. While much is known about the pathogenesis of chronic HIV infection, our knowledge is limited about the initial host- virus interactions in the gut mucosa an their potential impact on the viral dissemination, anti-viral mucosal immunity and mucosal response to other pathogens and commensal microbiota. The overall goal of the proposed research is to investigate early host-virus interactions at the gut mucosal site by (a) identifying mucosal cells and molecular signaling responsible for early sensing and response to the virus and their role in the induction of gut inflammation and subsequent viral dissemination and (b) functional mapping through experimentally intervening these early host-viral interactions. Using the simian immunodeficiency virus (SIV) model of AIDS, we recently identified previously unrecognized role of Paneth cells in early mucosal sensing and response to the virus and for potentially initiating the gut inflammation. Marked induction of IL-1? expression in Paneth cells at 2.5 days of SIV infection caused changes in the epithelial barrier structural integrity. The central hypothesis of this proposal is that Paneth cell sensing and response to virus-infected cells initially induces IL-1? signaling, and may drive early gut inflammation through gut epithelil disruption and mucosal T cell cycling that in turn will support exponential increase in viral dissemination and establish stable viral reservoirs. The experimental plans are based on our expertise in the SIV model, gut mucosal immunology and preliminary data on early gut mucosal responders to SIV infected cells. The goals of the proposed project will be achieved through two specific aims. Aim 1: To investigate the impact of Paneth cell sensing and establishment of early viral reservoirs. The effects of early immune responses to viral infection by gut immune and epithelial cell compartments and their contribution to further viral dissemination will be investigated through in vivo and in vitro intestinal analyses. Aim 2: Determine the impact of early anti- retroviral therapy (ART) and of IL-1? blockade in dampening Paneth cell mediated gut inflammation ? network and preventing/ reducing the viral dissemination. The proposed studies are highly relevant to the identification and characterization of early mucosal sensing and response networks that may drive gut inflammation and support an exponential spread of virus to mucosal immune targets and to understanding of the impact of intervening these events through ART and IL-1? inhibitor. Deciphering the mechanisms of the early spread of viral infection will provide novel targets of therapeutic intervention that will prevent or limit the establishment of early viral reservoirs.